U.S. patent number 7,261,735 [Application Number 09/887,464] was granted by the patent office on 2007-08-28 for local drug delivery devices and methods for maintaining the drug coatings thereon.
This patent grant is currently assigned to Cordis Corporation. Invention is credited to David Christian Lentz, Gerard H. Llanos.
United States Patent |
7,261,735 |
Llanos , et al. |
August 28, 2007 |
Local drug delivery devices and methods for maintaining the drug
coatings thereon
Abstract
Local drug delivery medical devices are utilized to deliver
therapeutic dosages of drugs, agents or compounds directly to the
site where needed. The local drug delivery medical devices utilize
various materials and coating methodologies to maintain the drugs,
agents or compounds on the medical device until delivered and
positioned.
Inventors: |
Llanos; Gerard H.
(Stewartsville, NJ), Lentz; David Christian (Weston,
FL) |
Assignee: |
Cordis Corporation (Miami
Lakes, FL)
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Family
ID: |
25391190 |
Appl.
No.: |
09/887,464 |
Filed: |
June 22, 2001 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20020165608 A1 |
Nov 7, 2002 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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09850482 |
May 7, 2001 |
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Current U.S.
Class: |
623/1.46;
623/1.42; 623/1.44 |
Current CPC
Class: |
A61B
17/0644 (20130101); A61B 17/11 (20130101); A61B
17/115 (20130101); A61F 2/91 (20130101); A61F
2/915 (20130101); A61K 31/436 (20130101); A61K
31/727 (20130101); A61K 45/06 (20130101); A61L
27/34 (20130101); A61L 31/10 (20130101); A61L
31/16 (20130101); A61L 27/34 (20130101); C08L
27/12 (20130101); A61L 31/10 (20130101); C08L
27/12 (20130101); A61K 31/436 (20130101); A61K
31/727 (20130101); A61B 17/00491 (20130101); A61B
17/0469 (20130101); A61B 2017/06028 (20130101); A61F
2/064 (20130101); A61F 2002/91541 (20130101); A61F
2250/0067 (20130101); A61F 2310/0097 (20130101); A61L
2300/41 (20130101); A61L 2300/416 (20130101); A61L
2300/42 (20130101); A61L 2300/606 (20130101); A61K
2300/00 (20130101); A61K 2300/00 (20130101) |
Current International
Class: |
A61F
2/06 (20060101) |
Field of
Search: |
;604/95.03,96.01,101.02,103.02,51-53,500,890.1,891.1
;623/11,1.42-1.48,1.16
;512/291,56,378,466,824,521,18,456,763,44,2,93.2,964
;424/122,423-424,240.22 |
References Cited
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WO 03/057218 |
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WO |
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|
Primary Examiner: Bianco; Patricia
Assistant Examiner: Nguyen; Camtu
Attorney, Agent or Firm: Evens; Carl J.
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part application of U.S.
application Ser. No. 09/850,482 filed May 7, 2001.
Claims
What is claimed is:
1. A local drug delivery apparatus comprising: a medical device for
implantation into a treatment site of a living organism; a layer
including a rapamycin in therapeutic dosages incorporated in a
polymeric matrix and affixed to the medical device for the
treatment of reactions by the living organism caused by the medical
device or the implantation thereof; and a distinct and separate
biocompatible, water soluble powder layer applied to an outermost
surface of the polymeric matrix configured to prevent the layer
affixed to the medical device from separating from the medical
device prior to implantation of the medical device at the treatment
site, the water-soluble powder comprising an anti-oxidant.
2. The local drug delivery apparatus according to claim 1, wherein
the medical device comprises an intraluminal medical device.
3. The local drug delivery apparatus according to claim 2, wherein
the intraluminal medical device comprises a stent.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the local administration of
drug/drug combinations for the prevention and treatment of vascular
disease, and more particularly to intraluminal medical devices for
the local delivery of drug/drug combinations for the prevention and
treatment of vascular disease caused by injury and methods for
maintaining the drug/drug combinations on the intraluminal medical
devices. The present invention also relates to medical devices
having drugs, agents or compounds affixed thereto to minimize or
substantially eliminate a biological organism's reaction to the
introduction of the medical device to the organism.
2. Discussion of the Related Art
Many individuals suffer from circulatory disease caused by a
progressive blockage of the blood vessels that profuse the heart
and other major organs with nutrients. More severe blockage of
blood vessels in such individuals often leads to hypertension,
ischemic injury, stroke, or myocardial infarction. Atherosclerotic
lesions, which limit or obstruct coronary blood flow, are the major
cause of ischemic heart disease. Percutaneous transluminal coronary
angioplasty is a medical procedure whose purpose is to increase
blood flow through an artery. Percutaneous transluminal coronary
angioplasty is the predominant treatment for coronary vessel
stenosis. The increasing use of this procedure is attributable to
its relatively high success rate and its minimal invasiveness
compared with coronary bypass surgery. A limitation associated with
percutaneous transluminal coronary angioplasty is the abrupt
closure of the vessel which may occur immediately after the
procedure and restenosis which occurs gradually following the
procedure. Additionally, restenosis is a chronic problem in
patients who have undergone saphenous vein bypass grafting. The
mechanism of acute occlusion appears to involve several factors and
may result from vascular recoil with resultant closure of the
artery and/or deposition of blood platelets and fibrin along the
damaged length of the newly opened blood vessel.
Restenosis after percutaneous transluminal coronary angioplasty is
a more gradual process initiated by vascular injury. Multiple
processes, including thrombosis, inflammation, growth factor and
cytokine release, cell proliferation, cell migration and
extracellular matrix synthesis each contribute to the restenotic
process.
While the exact mechanism of restenosis is not completely
understood, the general aspects of the restenosis process have been
identified. In the normal arterial wall, smooth muscle cells
proliferate at a low rate, approximately less than 0.1 percent per
day. Smooth muscle cells in the vessel walls exist in a contractile
phenotype characterized by eighty to ninety percent of the cell
cytoplasmic volume occupied with the contractile apparatus.
Endoplasmic reticulum, Golgi, and free ribosomes are few and are
located in the perinuclear region. Extracellular matrix surrounds
the smooth muscle cells and is rich in heparin-like
glycosylaminoglycans which are believed to be responsible for
maintaining smooth muscle cells in the contractile phenotypic state
(Campbell and Campbell, 1985).
Upon pressure expansion of an intracoronary balloon catheter during
angioplasty, smooth muscle cells within the vessel wall become
injured, initiating a thrombotic and inflammatory response. Cell
derived growth factors such as platelet derived growth factor,
basic fibroblast growth factor, epidermal growth factor, thrombin,
etc., released from platelets, invading macrophages and/or
leukocytes, or directly from the smooth muscle cells provoke a
proliferative and migratory response in medial smooth muscle cells.
These cells undergo a change from the contractile phenotype to a
synthetic phenotype characterized by only a few contractile
filament bundles, extensive rough endoplasmic reticulum, Golgi and
free ribosomes. Proliferation/migration usually begins within one
to two days post-injury and peaks several days thereafter (Campbell
and Campbell, 1987; Clowes and Schwartz, 1985).
Daughter cells migrate to the intimal layer of arterial smooth
muscle and continue to proliferate and secrete significant amounts
of extracellular matrix proteins. Proliferation, migration and
extracellular matrix synthesis continue until the damaged
endothelial layer is repaired at which time proliferation slows
within the intima, usually within seven to fourteen days
post-injury. The newly formed tissue is called neointima. The
further vascular narrowing that occurs over the next three to six
months is due primarily to negative or constrictive remodeling.
Simultaneous with local proliferation and migration, inflammatory
cells adhere to the site of vascular injury. Within three to seven
days post-injury, inflammatory cells have migrated to the deeper
layers of the vessel wall. In animal models employing either
balloon injury or stent implantation, inflammatory cells may
persist at the site of vascular injury for at least thirty days
(Tanaka et al., 1993; Edelman et al., 1998). Inflammatory cells
therefore are present and may contribute to both the acute and
chronic phases of restenosis.
Numerous agents have been examined for presumed anti-proliferative
actions in restenosis and have shown some activity in experimental
animal models. Some of the agents which have been shown to
successfully reduce the extent of intimal hyperplasia in animal
models include: heparin and heparin fragments (Clowes, A. W. and
Karnovsky M., Nature 265: 25 26, 1977; Guyton, J. R. et al., Circ.
Res., 46: 625 634,1980; Clowes, A. W. and Clowes, M. M., Lab.
Invest. 52: 611 616, 1985; Clowes, A. W. and Clowes, M. M., Circ.
Res. 58: 839 845, 1986; Majesky et al., Circ. Res. 61: 296 300,
1987; Snow et al., Am. J. Pathol. 137: 313 330, 1990; Okada, T. et
al., Neurosurgery 25: 92 98, 1989), colchicine (Currier, J. W. et
al., Circ. 80: 11 66, 1989), taxol (Sollot, S. J. et al., J. Clin.
Invest. 95: 1869 1876, 1995), angiotensin converting enzyme (ACE)
inhibitors (Powell, J. S. et al., Science, 245: 186 188, 1989),
angiopeptin (Lundergan, C. F. et al. Am. J. Cardiol. 17(Suppl.
B):132B 136B, 1991), cyclosporin A (Jonasson, L. et al., Proc.
Natl., Acad. Sci., 85: 2303, 1988), goat-anti-rabbit PDGF antibody
(Ferns, G. A. A., et al., Science 253: 1129 1132, 1991),
terbinafine (Nemecek, G. M. et al., J. Pharmacol. Exp. Thera. 248:
1167 1174, 1989), trapidil (Liu, M. W. et al., Circ. 81: 1089 1093,
1990), tranilast (Fukuyama, J. et al., Eur. J. Pharmacol. 318: 327
332, 1996), interferongamma (Hansson, G. K. and Holm, J., Circ. 84:
1266 1272, 1991), rapamycin (Marx, S. O. et al., Circ. Res. 76: 412
417, 1995), steroids (Colburn, M. D. et al., J. Vasc. Surg. 15: 510
518, 1992), see also Berk, B. C. et al., J. Am. Coll. Cardiol. 17:
111B 117B , 1991), ionizing radiation (Weinberger, J. et al., Int.
J. Rad. Onc. Biol. Phys. 36: 767 775, 1996), fusion toxins (Farb,
A. et al., Circ. Res. 80: 542 550, 1997) antisense oligonucleotides
(Simons, M. et al., Nature 359: 67 70,1992) and gene vectors
(Chang, M. W. et al., J. Clin. Invest. 96: 2260 2268, 1995).
Anti-proliferative action on smooth muscle cells in vitro has been
demonstrated for many of these agents, including heparin and
heparin conjugates, taxol, tranilast, colchicine, ACE inhibitors,
fusion toxins, antisense oligonucleotides, rapamycin and ionizing
radiation. Thus, agents with diverse mechanisms of smooth muscle
cell inhibition may have therapeutic utility in reducing intimal
hyperplasia.
However, in contrast to animal models, attempts in human
angioplasty patients to prevent restenosis by systemic
pharmacologic means have thus far been unsuccessful. Neither
aspirin-dipyridamole, ticlopidine, anti-coagulant therapy (acute
heparin, chronic warfarin, hirudin or hirulog), thromboxane
receptor antagonism nor steroids have been effective in preventing
restenosis, although platelet inhibitors have been effective in
preventing acute reocclusion after angioplasty (Mak and Topol,
1997; Lang et al., 1991; Popma et al., 1991). The platelet GP
IIb/IIIa receptor, antagonist, Reopro is still under study but has
not shown promising results for the reduction in restenosis
following angioplasty and stenting. Other agents, which have also
been unsuccessful in the prevention of restenosis, include the
calcium channel antagonists, prostacyclin mimetics, angiotensin
converting enzyme inhibitors, serotonin receptor antagonists, and
anti-proliferative agents. These agents must be given systemically,
however, and attainment of a therapeutically effective dose may not
be possible; anti-proliferative (or anti-restenosis) concentrations
may exceed the known toxic concentrations of these agents so that
levels sufficient to produce smooth muscle inhibition may not be
reached (Mak and Topol, 1997; Lang et al., 1991; Popma et al.,
1991).
Additional clinical trials in which the effectiveness for
preventing restenosis utilizing dietary fish oil supplements or
cholesterol lowering agents has been examined showing either
conflicting or negative results so that no pharmacological agents
are as yet clinically available to prevent post-angioplasty
restenosis (Mak and Topol, 1997; Franklin and Faxon, 1993: Serruys,
P. W. et al., 1993). Recent observations suggest that the
antilipid/antioxident agent, probucol may be useful in preventing
restenosis but this work requires confirmation (Tardif et al.,
1997; Yokoi, et al., 1997). Probucol is presently not approved for
use in the United States and a thirty-day pretreatment period would
preclude its use in emergency angioplasty. Additionally, the
application of ionizing radiation has shown significant promise in
reducing or preventing restenosis after angioplasty in patients
with stents (Teirstein et al., 1997). Currently, however, the most
effective treatments for restenosis are repeat angioplasty,
atherectomy or coronary artery bypass grafting, because no
therapeutic agents currently have Food and Drug Administration
approval for use for the prevention of post-angioplasty
restenosis.
Unlike systemic pharmacologic therapy, stents have proven useful in
significantly reducing restenosis. Typically, stents are
balloon-expandable slotted metal tubes (usually, but not limited
to, stainless steel), which, when expanded within the lumen of an
angioplastied coronary artery, provide structural support through
rigid scaffolding to the arterial wall. This support is helpful in
maintaining vessel lumen patency. In two randomized clinical
trials, stents increased angiographic success after percutaneous
transluminal coronary angioplasty, by increasing minimal lumen
diameter and reducing, but not eliminating, the incidence of
restenosis at six months (Serruys et al., 1994; Fischman et al.,
1994).
Additionally, the heparin coating of stents appears to have the
added benefit of producing a reduction in sub-acute thrombosis
after stent implantation (Serruys et al., 1996). Thus, sustained
mechanical expansion of a stenosed coronary artery with a stent has
been shown to provide some measure of restenosis prevention, and
the coating of stents with heparin has demonstrated both the
feasibility and the clinical usefulness of delivering drugs
locally, at the site of injured tissue.
As stated above, the use of heparin coated stents demonstrates the
feasibility and clinical usefulness of local drug delivery;
however, the manner in which the particular drug or drug
combination is affixed to the local delivery device will play a
role in the efficacy of this type of treatment. For example, the
processes and materials utilized to affix the drug/drug
combinations to the local delivery device should not interfere with
the operations of the drug/drug combinations. In addition, the
processes and materials utilized should be biocompatible and
maintain the drug/drug combinations on the local device through
delivery and over a given period of time. For example, removal of
the drug/drug combination during delivery of the local delivery
device may potentially cause failure of the device.
Accordingly, there exists a need for drug/drug combinations and
associated local delivery devices for the prevention and treatment
of vascular injury causing intimal thickening which is either
biologically induced, for example atherosclerosis, or mechanically
induced, for example, through percutaneous transluminal coronary
angioplasty. In addition, there exists a need for maintaining the
drug/drug combinations on the local delivery device through
delivery and positioning as well as ensuring that the drug/drug
combination is released in therapeutic dosages over a given period
of time.
SUMMARY OF THE INVENTION
The drug/drug combinations and associated local delivery devices of
the present invention provide a means for overcoming the
difficulties associated with the methods and devices currently in
use, as briefly described above. In addition, the methods for
maintaining the drug/drug combinations on the local delivery device
ensure that the drug/drug combinations reach the target site.
In accordance with one aspect, the present invention is directed to
a local drug delivery apparatus. The local drug delivery apparatus
comprises a medical device for implantation into a treatment site
of a living organism and at least one agent in therapeutic dosages
releasable affixed to the medical device for the treatment of
reactions by the living organism caused by the medical device or
the implantation thereof. The local delivery apparatus also
comprises a material for preventing the at least one agent from
separating from the medical device prior to implantation of the
medical device at the treatment site, the material being affixed to
at least one of the medical device or a delivery system for the
medical device.
In accordance with another aspect, the present invention is
directed to a local drug delivery apparatus. The local drug
delivery apparatus comprises a medical device for implantation into
a treatment site of a living organism and at least one agent in
therapeutic dosages releasably affixed to the medical device for
the treatment of reactions by the living organism caused by the
medical device or the implantation thereof, the at least one agent
being incorporated into a polymeric matrix. The local drug delivery
apparatus also comprises a material for preventing the at least one
agent from separating from the medical device prior to implantation
of the medical device at the treatment site, the material being
affixed to at least one of the medical device or a delivery system
for the medical device.
In accordance with another aspect, the present invention is
directed to a local drug delivery apparatus. The local drug
delivery apparatus comprises a medical device for implantation into
a treatment site of a living organism and at least one agent in
therapeutic dosages releasably affixed to the medical device for
the treatment of reactions by the living organism caused by the
medical device or the implantation thereof, the at least one agent
being incorporated into a polymeric matrix. The local drug delivery
apparatus also comprises a material for preventing the polymeric
matrix from adhering to itself when parts of the medical device
make contact with one another.
In accordance with another aspect, the present invention is
directed to a drug delivery device. The drug delivery device
comprises a medical device for implantation into a treatment site
of a living organism, and therapeutic dosages of one or more
anti-proliferatives, one or more anti-inflammatories, one or more
anti-coagulants, and one or more immunosuppressants releasably
affixed to the medical device for the treatment of reactions by the
living organism caused by the medical device or the implantation of
the medical device at the treatment site.
In accordance with another aspect, the present invention is
directed to a method for maintaining agents on a medical device
during implantation into a treatment site of a living organism. The
method comprises releasably affixing one or more agents in
therapeutic dosages to the medical device, treating one of the
medical device or the delivery device with a material for
preventing the one or more agents from separating from the medical
device during delivery and implantation of the medical device at
the treatment site, and loading the medical device into a delivery
device.
In accordance with another aspect, the present invention is
directed to a method for maintaining agents on a medical device
during implantation into a treatment site of a living organism. The
method comprises releasably affixing one or more agents in
therapeutic dosages to the medical device by incorporating the one
or more agents in at least one polymer, treating the medical device
with a material for preventing the polymer from adhering to itself
when parts of the medical device make contact, and loading the
medical device into a delivery device.
In accordance with another aspect, the present invention is
directed to a method for maintaining agents on a medical device
during implantation into a treatment site of a living organism. The
method comprises coating at least a portion of the medical device
with a primer layer, coating the primer layer with a first polymer
layer including cross-linking moieties, cross-linking the first
polymer layer to the primer layer, and releasably affixing one or
more agents in therapeutic dosages to the medical device by
incorporating the one or more agents in at least one polymer, the
polymer being similar in chemical composition to the first
polymer.
The local drug delivery devices and methods for maintaining the
drug coatings thereon of the present invention utilizes a
combination of materials to treat disease, and reactions by living
organisms due to the implantation of medical devices for the
treatment of disease or other conditions. The local delivery of
drugs, agents or compounds generally substantially reduces the
potential toxicity of the drugs, agents or compounds when compared
to systemic delivery while increasing their efficacy.
Drugs, agents or compounds may be affixed to any number of medical
devices to treat various diseases. The drugs, agents or compounds
may also be affixed to minimize or substantially eliminate the
biological organism's reaction to the introduction of the medical
device utilized to treat a separate condition. For example, stents
may be introduced to open coronary arteries or other body lumens
such as biliary ducts. The introduction of these stents cause a
smooth muscle cell proliferation effect as well as inflammation.
Accordingly, the stents may be coated with drugs to combat these
reactions.
In order to be effective, the drugs, agents or compounds should
preferably remain on the medical devices during delivery and
implantation. Accordingly, various coating techniques for creating
strong bonds between the drugs, agents or compounds may be
utilized. In addition, various materials may be utilized as surface
modifications to prevent the drugs, agents or compounds from coming
off prematurely.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing and other features and advantages of the invention
will be apparent from the following, more particular description of
preferred embodiments of the invention, as illustrated in the
accompanying drawings.
FIG. 1 is a view along the length of a stent (ends not shown) prior
to expansion showing the exterior surface of the stent and the
characteristic banding pattern.
FIG. 2 is a perspective view of the stent of FIG. 1 having
reservoirs in accordance with the present invention.
FIG. 3 is a cross-sectional view of a band of the stent of FIG. 1
having drug coatings thereon in accordance with a first exemplary
embodiment of the invention.
FIG. 4 is a cross-sectional view of a band of the stent of FIG. 1
having drug coatings thereon in accordance with a second exemplary
embodiment of the invention.
FIG. 5 is a cross-sectional view of a band of the stent of FIG. 1
having drug coatings thereon in accordance with a third exemplary
embodiment of the present invention.
FIG. 6 is a cross-sectional view of a balloon having a lubricious
coating affixed thereto in accordance with the present
invention.
FIG. 7 is a cross-sectional view of a band of the stent in FIG. 1
having a lubricious coating affixed thereto in accordance with the
present invention.
FIG. 8 is a cross-sectional view of a self-expanding stent in a
delivery device having a lubricious coating in accordance with the
present invention.
FIG. 9 is a cross-sectional view of a band of the stent in FIG. 1
having a modified polymer coating in accordance with the present
invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The drug/drug combinations and delivery devices of the present
invention may be utilized to effectively prevent and treat vascular
disease, and in particular, vascular disease caused by injury.
Various medical treatment devices utilized in the treatment of
vascular disease may ultimately induce further complications. For
example, balloon angioplasty is a procedure utilized to increase
blood flow through an artery and is the predominant treatment for
coronary vessel stenosis. However, as stated above, the procedure
typically causes a certain degree of damage to the vessel wall,
thereby potentially exacerbating the problem at a point later in
time. Although other procedures and diseases may cause similar
injury, the present invention will be described with respect to the
treatment of restenosis and related complications following
percutaneous transluminal coronary angioplasty.
While the invention will be described with respect to the treatment
of restenosis and related complications following percutaneous
transluminal coronary angioplasty, it is important to note that the
local delivery of drug/drug combinations may be utilized to treat a
wide variety of conditions utilizing any number of medical devices,
or to enhance the function and/or life of the device. For example,
intraocular lenses, placed to restore vision after cataract surgery
is often compromised by the formation of a secondary cataract. The
latter is often a result of cellular overgrowth on the lens surface
and can be potentially minimized by combining a drug or drugs with
the device. Other medical devices which often fail due to tissue
in-growth or accumulation of proteinaceous material in, on and
around the device, such as shunts for hydrocephalus, dialysis
grafts, colostomy bag attachment devices, ear drainage tubes, leads
for pace makers and implantable defibrillators can also benefit
from the device-drug combination approach. Devices which serve to
improve the structure and function of tissue or organ may also show
benefits when combined with the appropriate agent or agents. For
example, improved osteointegration of orthopedic devices to enhance
stabilization of the implanted device could potentially be achieved
by combining it with agents such as bonemorphogenic protein.
Similarly other surgical devices, sutures, staples, vertebral
disks, bone pins, suture anchors, hemostatic barriers, clamps,
screws, plates, clips, vascular implants; tissue adhesives and
sealants, tissue scaffolds, various types of dressings, bone
substitutes, intraluminal devices, and vascular supports could also
provide enhanced patient benefit using this drug-device combination
approach. Essentially, any type of medical device may be coated in
some fashion with a drug or drug combination which enhances
treatment over use of the singular use of the device or
pharmaceutical agent.
As stated previously, the implantation of a coronary stent in
conjunction with balloon angioplasty is highly effective in
treating acute vessel closure and may reduce the risk of
restenosis. Intravascular ultrasound studies (Mintz et al., 1996)
suggest that coronary stenting effectively prevents vessel
constriction and that most of the late luminal loss after stent
implantation is due to plaque growth, probably related to
neointimal hyperplasia. The late luminal loss after coronary
stenting is almost two times higher than that observed after
conventional balloon angioplasty. Thus, inasmuch as stents prevent
at least a portion of the restenosis process, a combination of
drugs, agents or compounds which prevents smooth muscle cell
proliferation, reduces inflammation and reduces coagulation or
prevents smooth muscle cell proliferation by multiple mechanisms,
reduces inflammation and reduces coagulation combined with a stent
may provide the most efficacious treatment for post-angioplasty
restenosis. The systemic use of drugs, agents or compounds in
combination with the local delivery of the same or different
drug/drug combinations may also provide a beneficial treatment
option.
The local delivery of drug/drug combinations from a stent has the
following advantages; namely, the prevention of vessel recoil and
remodeling through the scaffolding action of the stent and the
prevention of multiple components of neointimal hyperplasia or
restenosis as well as a reduction in inflammation and thrombosis.
This local administration of drugs, agents or compounds to stented
coronary arteries may also have additional therapeutic benefit. For
example, higher tissue concentrations of the drugs, agents or
compounds can be achieved utilizing local delivery, rather than
systemic administration. In addition, reduced systemic toxicity may
be achieved utilizing local delivery rather than systemic
administration while maintaining higher tissue concentrations. Also
in utilizing local delivery from a stent rather than systemic
administration, a single procedure may suffice with better patient
compliance. An additional benefit of combination
drug/agent/compound therapy may be to reduce the dose of each of
the therapeutic drugs, agents or compounds, thereby limiting their
toxicity, while still achieving a reduction in restenosis,
inflammation and thrombosis. Local stent-based therapy is therefore
a means of improving the therapeutic ratio (efficacy/toxicity) of
anti-restenosis, anti-inflammatory, anti-thrombotic drugs, agents
or compounds.
There are a multiplicity of different stents that may be utilized
following percutaneous transluminal coronary angioplasty. Although
any number of stents may be utilized in accordance with the present
invention, for simplicity, one particular stent will be described
in exemplary embodiments of the present invention. The skilled
artisan will recognize that any number of stents may be utilized in
connection with the present invention. In addition, as stated
above, other medical devices may be utilized.
A stent is commonly used as a tubular structure left inside the
lumen of a duct to relieve an obstruction. Commonly, stents are
inserted into the lumen in a non-expanded form and are then
expanded autonomously, or with the aid of a second device in situ.
A typical method of expansion occurs through the use of a
catheter-mounted angioplasty balloon which is inflated within the
stenosed vessel or body passageway in order to shear and disrupt
the obstructions associated with the wall components of the vessel
and to obtain an enlarged lumen.
FIG. 1 illustrates an exemplary stent 100 which may be utilized in
accordance with an exemplary embodiment of the present invention.
The expandable cylindrical stent 100 comprises a fenestrated
structure for placement in a blood vessel, duct or lumen to hold
the vessel, duct or lumen open, more particularly for protecting a
segment of artery from restenosis after angioplasty. The stent 100
may be expanded circumferentially and maintained in an expanded
configuration, that is circumferentially or radially rigid. The
stent 100 is axially flexible and when flexed at a band, the stent
100 avoids any externally-protruding component parts.
The stent 100 generally comprises first and second ends with an
intermediate section therebetween. The stent 100 has a longitudinal
axis and comprises a plurality of longitudinally disposed bands
102, wherein each band 102 defines a generally continuous wave
along a line segment parallel to the longitudinal axis. A plurality
of circumferentially arranged links 104 maintain the bands 102 in a
substantially tubular structure. Essentially, each longitudinally
disposed band 102 is connected at a plurality of periodic
locations, by a short circumferentially arranged link 104 to an
adjacent band 102. The wave associated with each of the bands 102
has approximately the same fundamental spatial frequency in the
intermediate section, and the bands 102 are so disposed that the
wave associated with them are generally aligned so as to be
generally in phase with one another. As illustrated in the figure,
each longitudinally arranged band 102 undulates through
approximately two cycles before there is a link to an adjacent band
102.
The stent 100 may be fabricated utilizing any number of methods.
For example, the stent 100 may be fabricated from a hollow or
formed stainless steel tube that may be machined using lasers,
electric discharge milling, chemical etching or other means. The
stent 100 is inserted into the body and placed at the desired site
in an unexpanded form. In one embodiment, expansion may be effected
in a blood vessel by a balloon catheter, where the final diameter
of the stent 100 is a function of the diameter of the balloon
catheter used.
It should be appreciated that a stent 100 in accordance with the
present invention may be embodied in a shape-memory material,
including, for example, an appropriate alloy of nickel and titanium
or stainless steel. In this embodiment after the stent 100 has been
formed it may be compressed so as to occupy a space sufficiently
small as to permit its insertion in a blood vessel or other tissue
by insertion means, wherein the insertion means include a suitable
catheter, or flexible rod. On emerging from the catheter, the stent
100 may be configured to expand into the desired configuration
where the expansion is automatic or triggered by a change in
pressure, temperature or electrical stimulation.
FIG. 2 illustrates an exemplary embodiment of the present invention
utilizing the stent 100 illustrated in FIG. 1. As illustrated, the
stent 100 may be modified to comprise one or more reservoirs 106.
Each of the reservoirs 106 may be opened or closed as desired.
These reservoirs 106 may be specifically designed to hold the
drug/drug combinations to be delivered. Regardless of the design of
the stent 100, it is preferable to have the drug/drug combination
dosage applied with enough specificity and a sufficient
concentration to provide an effective dosage in the lesion area. In
this regard, the reservoir size in the bands 102 is preferably
sized to adequately apply the drug/drug combination dosage at the
desired location and in the desired amount.
In an alternate exemplary embodiment, the entire inner and outer
surface of the stent 100 may be coated with drug/drug combinations
in therapeutic dosage amounts. A detailed description of a drug for
treating restenosis, as well as exemplary coating techniques, is
described below. It is, however, important to note that the coating
techniques may vary depending on the drug/drug combinations. Also,
the coating techniques may vary depending on the material
comprising the stent or other intraluminal medical device.
Rapamycin is a macroyclic triene antibiotic produced by
streptomyces hygroscopicus as disclosed in U.S. Pat. No. 3,929,992.
It has been found that rapamycin among other things inhibits the
proliferation of vascular smooth muscle cells in vivo. Accordingly,
rapamycin may be utilized in treating intimal smooth muscle cell
hyperplasia, restenosis, and vascular occlusion in a mammal,
particularly following either biologically or mechanically mediated
vascular injury, or under conditions that would predispose a mammal
to suffering such a vascular injury. Rapamycin functions to inhibit
smooth muscle cell proliferation and does not interfere with the
re-endothelialization of the vessel walls.
Rapamycin reduces vascular hyperplasia by antagonizing smooth
muscle proliferation in response to mitogenic signals that are
released during an angioplasty induced injury. Inhibition of growth
factor and cytokine mediated smooth muscle proliferation at the
late GI phase of the cell cycle is believed to be the dominant
mechanism of action of rapamycin. However, rapamycin is also known
to prevent T-cell proliferation and differentiation when
administered systemically. This is the basis for its
immunosuppresive activity and its ability to prevent graft
rejection.
As used herein, rapamycin includes rapamycin and all analogs,
derivatives and congeners that find FKBP12 and possesses the same
pharmacologic properties as rapamycin.
Although the anti-proliferative effects of rapamycin may be
achieved through systemic use, superior results may be achieved
through the local delivery of the compound. Essentially, rapamycin
works in the tissues, which are in proximity to the compound, and
has diminished effect as the distance from the delivery device
increases. In order to take advantage of this effect, one would
want the rapamycin in direct contact with the lumen walls.
Accordingly, in a preferred embodiment, the rapamycin is
incorporated onto the surface of the stent or portions thereof.
Essentially, the rapamycin is preferably incorporated into the
stent 100, illustrated in FIG. 1, where the stent 100 makes contact
with the lumen wall.
Rapamycin may be incorporated into or affixed to the stent in a
number of ways. In the exemplary embodiment, the rapamycin is
directly incorporated into a polymeric matrix and sprayed onto the
outer surface of the stent. The rapamycin elutes from the polymeric
matrix over time and enters the surrounding tissue. The rapamycin
preferably remains on the stent for at least three days up to
approximately six months, and more preferably between seven and
thirty days.
Any number of non-erodible polymers may be utilized in conjunction
with the rapamycin. In the exemplary embodiment, the polymeric
matrix comprises two layers. The base layer comprises a solution of
ethylene-co-vinylacetate and polybutylmethacrylate. The rapamycin
is incorporated into this base layer. The outer layer comprises
only polybutylmethacrylate and acts as a diffusion barrier to
prevent the rapamycin from eluting too quickly. The thickness of
the outer layer or top coat determines the rate at which the
rapamycin elutes from the matrix. Essentially, the rapamycin elutes
from the matrix by diffusion through the polymer molecules.
Polymers are permeable, thereby allowing solids, liquids and gases
to escape therefrom. The total thickness of the polymeric matrix is
in the range from about 1 micron to about 20 microns or
greater.
The ethylene-co-vinylacetate, polybutylmethacrylate and rapamycin
solution may be incorporated into or onto the stent in a number of
ways. For example, the solution may be sprayed onto the stent or
the stent may be dipped into the solution. Other methods include
spin coating and RF-plasma polymerization. In one exemplary
embodiment, the solution is sprayed onto the stent and then allowed
to dry. In another exemplary embodiment, the solution may be
electrically charged to one polarity and the stent electrically
changed to the opposite polarity. In this manner, the solution and
stent will be attracted to one another. In using this type of
spraying process, waste may be reduced and more precise control
over the thickness of the coat may be achieved.
Since rapamycin acts by entering the surrounding tissue, it s
preferably only affixed to the surface of the stent making contact
with one tissue. Typically, only the outer surface of the stent
makes contact with the tissue. Accordingly, in a preferred
embodiment, only the outer surface of the stent is coated with
rapamycin.
The circulatory system, under normal conditions, has to be
self-sealing, otherwise continued blood loss from an injury would
be life threatening. Typically, all but the most catastrophic
bleeding is rapidly stopped though a process known as hemostasis.
Hemostasis occurs through a progression of steps. At high rates of
flow, hemostasis is a combination of events involving platelet
aggregation and fibrin formation. Platelet aggregation leads to a
reduction in the blood flow due to the formation of a cellular plug
while a cascade of biochemical steps leads to the formation of a
fibrin clot.
Fibrin clots, as stated above, form in response to injury. There
are certain circumstances where blood clotting or clotting in a
specific area may pose a health risk. For example, during
percutaneous transluminal coronary angioplasty, the endothelial
cells of the arterial walls are typically injured, thereby exposing
the sub-endothelial cells. Platelets adhere to these exposed cells.
The aggregating platelets and the damaged tissue initiate further
biochemical process resulting in blood coagulation. Platelet and
fibrin blood clots may prevent the normal flow of blood to critical
areas. Accordingly, there is a need to control blood clotting in
various medical procedures. Compounds that do not allow blood to
clot are called anti-coagulants. Essentially, an anticoagulant is
an inhibitor of thrombin formation or function. These compounds
include drugs such as heparin and hirudin. As used herein, heparin
includes all direct or indirect inhibitors of thrombin or Factor
Xa.
In addition to being an effective anti-coagulant, heparin has also
been demonstrated to inhibit smooth muscle cell growth in vivo.
Thus, heparin may be effectively utilized in conjunction with
rapamycin in the treatment of vascular disease. Essentially, the
combination of rapamycin and heparin may inhibit smooth muscle cell
growth via two different mechanisms in addition to the heparin
acting as an anti-coagulant.
Because of its multifunctional chemistry, heparin may be
immobilized or affixed to a stent in a number of ways. For example,
heparin may be immobilized onto a variety of surfaces by various
methods, including the photolink methods set forth in U.S. Pat.
Nos. 3,959,078 and 4,722,906 to Guire et al. and U.S. Pat. Nos.
5,229,172; 5,308,641; 5,350,800 and 5,415,938 to Cahalan et al.
Heparinized surfaces have also been achieved by controlled release
from a polymer matrix, for example, silicone rubber, as set forth
in U.S. Pat. Nos. 5,837,313; 6,099,562 and 6,120,536 to Ding et
al.
In one exemplary embodiment, heparin may be immobilized onto the
stent as briefly described below. The surface onto which the
heparin is to be affixed is cleaned with ammonium peroxidisulfate.
Once cleaned, alternating layers of polyethylenimine and dextran
sulfate are deposited thereon. Preferably, four layers of the
polyethylenimine and dextran sulfate are deposited with a final
layer of polyethylenimine. Aldehyde-end terminated heparin is then
immobilized to this final layer and stabilized with sodium
cyanoborohydride. This process is set forth in U.S. Pat. Nos.
4,613,665; 4,810,784 to Larm and 5,049,403 to Larm et al.
Unlike rapamycin, heparin acts on circulating proteins in the blood
and heparin need only make contact with blood to be effective.
Accordingly, if used in conjunction with a medical device, such as
a stent, it would preferably be only on the side that comes into
contact with the blood. For example, if heparin were to be
administered via a stent, it would only have to be on the inner
surface of the stent to be effective.
In an exemplary embodiment of the invention, a stent may be
utilized in combination with rapamycin and heparin to treat
vascular disease. In this exemplary embodiment, the heparin is
immobilized to the inner surface of the stent so that it is in
contact with the blood and the rapamycin is immobilized to the
outer surface of the stent so that it is in contact with the
surrounding tissue. FIG. 3 illustrates a cross-section of a band
102 of the stent 100 illustrated in FIG. 1. As illustrated, the
band 102 is coated with heparin 108 on its inner surface 110 and
with rapamycin 112 on its outer surface 114.
In an alternate exemplary embodiment, the stent may comprise a
heparin layer immobilized on its inner surface, and rapamycin and
heparin on its outer surface. Utilizing current coating techniques,
heparin tends to form a stronger bond with the surface it is
immobilized to then does rapamycin. Accordingly, it may be possible
to first immobilize the rapamycin to the outer surface of the stent
and then immobilize a layer of heparin to the rapamycin layer. In
this embodiment, the rapamycin may be more securely affixed to the
stent while still effectively eluting from its polymeric matrix,
through the heparin and into the surrounding tissue. FIG. 4
illustrates a cross-section of a band 102 of the stent 100
illustrated in FIG. 1. As illustrated, the band 102 is coated with
heparin 108 on its inner surface 110 and with rapamycin 112 and
heparin 108 on its outer surface 114.
There are a number of possible ways to immobilize, i.e., entrapment
or covalent linkage with an erodible bond, the heparin layer to the
rapamycin layer. For example, heparin may be introduced into the
top layer of the polymeric matrix. In other embodiments, different
forms of heparin may be directly immobilized onto the top coat of
the polymeric matrix, for example, as illustrated in FIG. 5. As
illustrated, a hydrophobic heparin layer 116 may be immobilized
onto the top coat layer 118 of the rapamycin layer 112. A
hydrophobic form of heparin is utilized because rapamycin and
heparin coatings represent incompatible coating application
technologies. Rapamycin is an organic solvent-based coating and
heparin is a water-based coating.
As stated above, a rapamycin coating may be applied to stents by a
dip, spray or spin coating method, and/or any combination of these
methods. Various polymers may be utilized. For example, as
described above, polyethylene-co-vinyl acetate and polybutyl
methacrylate blends may be utilized. Other polymers may also be
utilized, but not limited to, for example, polyvinylidene
fluoride-co-hexafluoropropylene and polyethylbutyl
methacrylate-co-hexyl methacrylate. Also as described above,
barrier or top coatings may also be applied to modulate the
dissolution of rapamycin from the polymer matrix. In the exemplary
embodiment described above, a thin layer of heparin is applied to
the surface of the polymeric matrix. Because these polymer systems
are hydrophobic and incompatible with the hydrophilic heparin,
appropriate surface modifications may be required.
The application of heparin to the surface of the polymeric matrix
may be performed in various ways and utilizing various
biocompatible materials. For example, in one embodiment, in water
or alcoholic solutions, polyethylene imine may be applied on the
stents, with care not to degrade the rapamycin (e.g., pH<7, low
temperature), followed by the application of sodium heparinate in
aqueous or alcoholic solutions. As an extension of this surface
modification, covalent heparin may be linked on polyethylene imine
using amide-type chemistry (using a carbondiimide activator, e.g.
EDC) or reductive amination chemistry (using CBAS-heparin and
sodium cyanoborohydride for coupling). In another exemplary
embodiment, heparin may be photolinked on the surface, if it is
appropriately grafted with photo initiator moieties. Upon
application of this modified heparin formulation on the covalent
stent surface, light exposure causes cross-linking and
immobilization of the heparin on the coating surface. In yet
another exemplary embodiment, heparin may be complexed with
hydrophobic quaternary ammonium salts, rendering the molecule
soluble in organic solvents (e.g. benzalkonium heparinate,
troidodecylmethylammonium heparinate). Such a formulation of
heparin may be compatible with the hydrophobic rapamycin coating,
and may be applied directly on the coating surface, or in the
rapamycin/hydrophobic polymer formulation.
It is important to note that the stent may be formed from any
number of materials, including various metals, polymeric materials
and ceramic materials. Accordingly, various technologies may be
utilized to immobilize the various drugs, agent, compound
combinations thereon. In addition, the drugs, agents or compounds
may be utilized in conjunction with other percutaneously delivered
medical devices such as grafts and profusion balloons.
In addition to utilizing an anti-proliferative and anti-coagulant,
anti-inflammatories may also be utilized in combination therewith.
One example of such a combination would be the addition of an
anti-inflammatory corticosteroid such as dexamethasone with an
anti-proliferative, such as rapamycin, cladribine, vincristine,
taxol, or a nitric oxide donor and an anti-coagulant, such as
heparin. Such combination therapies might result in a better
therapeutic effect, i.e., less proliferation as well as less
inflammation, a stimulus for proliferation, than would occur with
either agent alone. The delivery of a stent comprising an
anti-proliferative, anti-coagulant, and an anti-inflammatory to an
injured vessel would provide the added therapeutic benefit of
limiting the degree of local smooth muscle cell proliferation,
reducing a stimulus for proliferation, i.e., inflammation and
reducing the effects of coagulation thus enhancing the
restenosis-limiting action of the stent.
In other exemplary embodiments of the inventions, growth factor or
cytokine signal transduction inhibitor, such as the ras inhibitor,
R115777, or a tyrosine kinase inhibitor, such as tyrphostin, might
be combined with an antiproliferative agent such as taxol,
vincristine or rapamycin so that proliferation of smooth muscle
cells could be inhibited by different mechanisms. Alternatively, an
anti-proliferative agent such as taxol, vincristine or rapamycin
could be combined with an inhibitor of extracellular matrix
synthesis such as halofuginone. In the above cases, agents acting
by different mechanisms could act synergistically to reduce smooth
muscle cell proliferation and vascular hyperplasia. This invention
is also intended to cover other combinations of two or more such
drug agents. As mentioned above, such drugs, agents or compounds
could be administered systemically, delivered locally via drug
delivery catheter, or formulated for delivery from the surface of a
stent, or given as a combination of systemic and local therapy.
In addition to anti-proliferatives, anti-inflammatories and
anti-coagulants, other drugs, agents or compounds may be utilized
in conjunction with the medical devices. For example,
immunosuppressants may be utilized alone or in combination with
these other drugs, agents or compounds. Also modified genes in
viral and non-viral gene introducers may also be introduced locally
via a medical device.
As described above, various drugs, agents or compounds may be
locally delivered via medical devices. For example, rapamycin and
heparin may be delivered by a stent to reduce restenosis,
inflammation, and coagulation. Various techniques for immobilizing
the drugs, agents or compounds are discussed above, however,
maintaining the drugs, agents or compounds on the medical devices
during delivery and positioning is critical to the success of the
procedure or treatment. For example, removal of the drug, agent or
compound coating during delivery of the stent can potentially cause
failure of the device. For a self-expanding stent, the retraction
of the restraining sheath may cause the drugs, agents or compounds
to rub off the stent. For a balloon expandable stent, the expansion
of the balloon may cause the drugs, agents or compounds to simply
delaminate from the stent through contact with the balloon or via
expansion. Therefore, prevention of this potential problem is
important to have a successful therapeutic medical device, such as
a stent.
There are a number of approaches that may be utilized to
substantially reduce the above-described problem. In one exemplary
embodiment, a lubricant or mold release agent may be utilized. The
lubricant or mold release agent may comprise any suitable
biocompatible lubricious coating. An exemplary lubricious coating
may comprise silicone. In this exemplary embodiment, a solution of
the silicone base coating may be introduced onto the balloon
surface, onto the polymeric matrix, and/or onto the inner surface
of the sheath of a self-expanding stent delivery apparatus and
allowed to air cure. Alternately, the silicone based coating may be
incorporated into the polymeric matrix. It is important to note,
however, that any number of lubricious materials may be utilized,
with the basic requirements being that the material be
biocompatible, that the material not interfere with the
actions/effectiveness of the drugs, agents or compounds and that
the material not interfere with the materials utilized to
immobilize the drugs, agents or compounds on the medical device. It
is also important to note that one or more, or all of the
above-described approaches may be utilized in combination.
Referring now to FIG. 6, there is illustrated a balloon 200 of a
balloon catheter that may be utilized to expand a stent in situ. As
illustrated, the balloon 200 comprises a lubricious coating 202.
The lubricious coating 202 functions to minimize or substantially
eliminate the adhesion between the balloon 200 and the coating on
the medical device. In the exemplary embodiment described above,
the lubricious coating 202 would minimize or substantially
eliminate the adhesion between the balloon 200 and the heparin or
rapamycin coating. The lubricious coating 202 may be attached to
and maintained on the balloon 200 in any number of ways including
but not limited to dipping, spraying, brushing or spin coating of
the coating material from a solution or suspension followed by
curing or solvent removal step as needed.
Materials such as synthetic waxes, e.g. diethyleneglycol
monostearate, hydrogenated castor oil, oleic acid, stearic acid,
zinc stearate, calcium stearate, ethylenebis (stearamide), natural
products such as paraffin wax, spermaceti wax, carnuba wax, sodium
alginate, ascorbic acid and flour, fluorinated compounds such as
perfluoroalkanes, perfluorofatty acids and alcohol, synthetic
polymers such as silicones e.g. polydimethylsiloxane,
polytetrafluoroethylene, polyfluoroethers, polyalkylglycol e.g.
polyethylene glycol waxes, and inorganic materials such as talc,
kaolin, mica, and silica may be used to prepare these coatings.
Vapor deposition polymerization e.g. parylene-C deposition, or
RF-plasma polymerization of perflouroalkenes can also be used to
prepare these lubricious coatings.
FIG. 7 illustrates a cross-section of a band 102 of the stent 100
illustrated in FIG. 1. In this exemplary embodiment, the lubricious
coating 300 is immobilized onto the outer surface of the polymeric
coating. As described above, the drugs, agents or compounds may be
incorporated into a polymeric matrix. The stent band 102
illustrated in FIG. 7 comprises a base coat 302 comprising a
polymer and rapamycin and a top coat 304 or diffusion layer 304
also comprising a polymer. The lubricious coating 300 is affixed to
the top coat 302 by any suitable means, including but not limited
to spraying, brushing, dipping or spin coating of the coating
material from a solution or suspension with or without the polymers
used to create the top coat, followed by curing or solvent removal
step as needed. Vapor deposition polymerization and RF-plasma
polymerization may also be used to affix those lubricious coating
materials that lend themselves to this deposition method, to the
top coating. In an alternate exemplary embodiment, the lubricious
coating may be directly incorporated into the polymeric matrix.
If a self-expanding stent is utilized, the lubricious coating may
be affixed to the inner surface of the restraining sheath. FIG. 8
illustrates a self-expanding stent 400 within the lumen of a
delivery apparatus sheath 402. As illustrated, a lubricious coating
404 is affixed to the inner surfaces of the sheath 402.
Accordingly, upon deployment of the stent 400, the lubricious
coating 404 preferably minimizes or substantially eliminates the
adhesion between the sheath 402 and the drug, agent or compound
coated stent 400.
In an alternate approach, physical and/or chemical cross-linking
methods may be applied to improve the bond strength between the
polymeric coating containing the drugs, agents or compounds and the
surface of the medical device or between the polymeric coating
containing the drugs, agents or compounds and a primer.
Alternately, other primers applied by either traditional coating
methods such as dip, spray or spin coating, or by RF-plasma
polymerization may also be used to improve bond strength. For
example, as shown in FIG. 9, the bond strength can be improved by
first depositing a primer layer 500 such as vapor polymerized
parylene-C on the device surface, and then placing a second layer
502 which comprises a polymer that is similar in chemical
composition to the one or more of the polymers that make up the
drug-containing matrix 504, e.g., polyethylene-co-vinyl acetate or
polybutyl methacrylate but has been modified to contain
cross-linking moieties. This secondary layer 502 is then
cross-linked to the primer after exposure to ultraviolet light. It
should be noted that anyone familiar with the art would recognize
that a similar outcome could be achieved using cross-linking agents
that are activated by heat with or without the presence of an
activating agent. The drug-containing matrix 504 is then layered
onto the secondary layer 502 using a solvent that swells, in part
or wholly, the secondary layer 502. This promotes the entrainment
of polymer chains from the matrix into the secondary layer 502 and
conversely from the secondary layer 502 into the drug-containing
matrix 504. Upon removal of the solvent from the coated layers, an
interpenetrating or interlocking network of the polymer chains is
formed between the layers thereby increasing the adhesion strength
between them. A top coat 506 is used as described above.
A related problem occurs in medical devices such as stents. In the
drug-coated stents crimped state, some struts come into contact
with each other and when the stent is expanded, the motion causes
the polymeric coating comprising the drugs, agents or compounds to
stick and stretch. This action may potentially cause the coating to
separate from the stent in certain areas. The predominant mechanism
of the coating self-adhesion is believed to be due to mechanical
forces. When the polymer comes in contact with itself, its chains
can tangle causing the mechanical bond, similar to Velcro.RTM..
Certain polymers do not bond with each other, for example,
fluoropolymers. For other polymers, however, powders may be
utilized. In other words, a powder may be applied to the one or
more polymers incorporating the drugs, agents or other compounds on
the surfaces of the medical device to reduce the mechanical bond.
Any suitable biocompatible material which does not interfere with
the drugs, agents, compounds or materials utilized to immobilize
the drugs, agents or compounds onto the medical device may be
utilized. For example, a dusting with a water soluble powder may
reduce the tackiness of the coatings surface and this will prevent
the polymer from sticking to itself thereby reducing the potential
for delamination. The powder should be water-soluble so that it
does not present an emboli risk. The powder may comprise an
anti-oxidant, such as vitamin C, or it may comprise an
anti-coagulant, such as aspirin or heparin. An advantage of
utilizing an anti-oxidant may be in the fact that the anti-oxidant
may preserve the other drugs, agents or compounds over longer
periods of time.
Although shown and described is what is believed to be the most
practical and preferred embodiments, it is apparent that departures
from specific designs and methods described and shown will suggest
themselves to those skilled in the art and may be used without
departing from the spirit and scope of the invention. The present
invention is not restricted to the particular constructions
described and illustrated, but should be constructed to cohere with
all modifications that may fall within the scope of the appended
claims.
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